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Ann Thorac Surg 2004;77:635-642
© 2004 The Society of Thoracic Surgeons
a Division of Thoracic Surgery, Duke University Medical Center, Durham, North Carolina, USA
b Duke Center for Clinical Health Policy Research, Duke University Medical Center, Durham, North Carolina, USA
c Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA
d Bayer Corporation, West Haven, Connecticut, USA
e National Cancer Institute, Bethesda, Maryland, USA
Accepted for publication June 23, 2003.
* Address reprint requests to Dr Smith, Department of Surgery, Duke University Medical Center, Box 3442, Durham, NC 27710, USA.
e-mail: smith058{at}mc.duke.edu
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Abstract |
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 Top Abstract IntroductionMaterial and methodsResultsCommentConclusionsAcknowledgmentsReferences |
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METHODS: To estimate CABG admission costs, resource utilization and clinical data from aprotinin clinical trials were combined with unit costs estimated from a Duke University–based cost model. Lifetime medical costs of stroke and acute myocardial infarction were based on previous research.
RESULTS: Relative to placebo, the differences in total perioperative cost for primary CABG patients receiving full-dose or half-dose aprotinin were not significant. When lifetime medical costs of complications were considered, total costs in full-dose and half-dose aprotinin-treated patients were not different relative to that of placebo. Total perioperative cost was significantly lower for repeat CABG patients treated with aprotinin, with savings of $2,058 for full-dose and $2,122 for half-dose patients when compared with placebo. Taking lifetime costs of stroke and acute myocardial infarction into consideration, the cost savings estimates were $6,044 for full-dose patients and $4,483 for half-dose patients, due to substantially higher lifetime stroke costs incurred by the placebo patients.
CONCLUSIONS: Using this cost model, use of full-dose and half-dose aprotinin in primary CABG patients was cost neutral during hospital admission, whereas both dosing regimens were significantly cost saving in reoperative CABG patients. Additional lifetime cost savings were realized relative to placebo due to reduced complication costs, particularly with the full-dose regimen. As the full kallikrein-inhibiting dose of aprotinin has been shown to be safe and effective, the current results support its use in both primary and repeat CABG surgery. No demonstrable economic advantage was observed with the half-dose aprotinin regimen.
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Introduction |
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TopAbstractIntroductionMaterial and methodsResultsCommentConclusionsAcknowledgmentsReferences |
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Aprotinin (Trasylol, Bayer Corporation, West Haven CT), a broad-spectrum serine protease inhibitor that inhibits the systemic inflammatory response associated with cardiopulmonary bypass [7], is widely used in CABG surgery. Prospective, randomized, placebo-controlled trials have consistently demonstrated that full-dose aprotinin reduces blood loss and transfusion requirements associated with CABG surgery [8–12]. Use of full-dose aprotinin in CABG reduces reoperations for bleeding [13] and has also been reported to be associated with a reduced incidence of stroke [9, 14, 15].
The current investigation assesses the tradeoff between the cost of aprotinin and cost-saving benefits that it may provide for both primary and repeat CABG patients. Two central questions are addressed. First, based on resource utilization data from clinical trials, is aprotinin associated with lower overall medical care costs? Second, does an economic dose-response relationship exist, such that higher aprotinin dose and the resulting increased drug cost alter the economic benefit?
This economic analysis examines cost impact of aprotinin use from both a short- and long-term perspective. The primary analysis addresses the short-term perspective through examining only perioperative costs, defined as those incurred during the hospital admission for CABG. Postoperative lifetime costs, including costs of blood transfusion complications (ie, transfusion-related reaction as well as posttransfusion infection), stroke, and acute myocardial infarction (AMI), were included when addressing the long-term perspective.
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Material and methods |
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TopAbstractIntroductionMaterial and methodsResultsCommentConclusionsAcknowledgmentsReferences |
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Clinical data
All clinical trial data on CABG surgery patients submitted by Bayer Pharmaceuticals Corporation (West Haven, CT) to the Food and Drug Administration (FDA) supporting licensure of Trasylol (aprotinin injection) were supplied by Bayer for use in the economic analysis (total, N = 2,057). Data were originally collected in seven prospective, randomized, double-blind, placebo-controlled trials evaluating aprotinin use in CABG surgery at 39 sites, from January 1990 to May 1995. Three clinical options were considered: full-dose aprotinin (load, 2,000,000 KIU; pump prime, 2,000,000 KIU; continuous infusion 500,000 KIU/h), half-dose aprotinin (load, 1,000,000 KIU; pump prime, 1,000,000 KIU; continuous infusion 250,000 KIU/h), and placebo. Two trials examined only primary CABG patients [8, 16], two trials included only repeat CABG patients [9, 11], whereas one evaluated primary and repeat CABG [10]. Inclusion criteria included those patients scheduled to have isolated CABG (no valve or combined procedures), male and nonpregnant female gender, more than 18 years of age, and willing and able to give informed consent. Exclusion criteria included patients with a history of bleeding diathesis, known hematological abnormality, those refusing blood transfusion, or allergies to either bovine products or aprotinin. Cardiopulmonary bypass techniques were standard and heparin dosing ranged from 300 to 400 IU/kg. Activated clotting time was determined by an automated heparin-protamine titration device. The indications for red blood cell transfusion were established per protocol (operative, hematocrit 18%; postoperative, 21% to 25%), although allogeneic blood transfusion was allowed at any time if required by the patient's clinical condition. Intra- and postoperative blood conservation techniques and postoperative ICU procedures were those routinely used at each participating institution. Patient demographics, cardiac-specific and general medical history, details of surgery, and adverse event information were collected on standardized case report forms. Data were maintained as SAS data sets and analyzed using SAS software (SAS Institute, Cary, NC).
Patients eligible for safety analysis by trial criteria were used to determine stroke, AMI, and in-hospital death rates, whereas patients eligible for efficacy analysis were used to determine resource utilization rates. Data were pooled across the studies into two mutually exclusive groups of patients, primary CABG and repeat CABG, whose participants received full-dose aprotinin, half-dose aprotinin, or an equal volume placebo (Table 1). Trial participants were assumed to be "exchangeable" statistically within the pooled dataset. The rate of AMI was determined by a blinded central laboratory based on predetermined electrocardiogram (ECG) and enzyme results for patients from selected studies (primary CABG: full-dose aprotinin, n = 578; half-dose aprotinin, n = 173; placebo, n = 594; repeat CABG: full-dose aprotinin, n = 68; half-dose aprotinin, n = 68; placebo, n = 67) [16]. Stroke was clinically identified by the investigator as a new persistent neurologic deficit occurring during hospitalization or any follow-up period required by protocol. Actual reports of stroke ranged from the day of surgery to 20 days after surgery (70% before day 4, 90% before day 10).
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Data analysis
For each resource unit (ie, blood product type, time in surgery, ICU length of stay, and post-ICU length of stay) analysis of variance based on ranked data for blood product usage was used to test the null hypothesis that usage was the same across the treatment arms. The Mantel-Haenszel statistic or Fisher's exact test was used to test whether differences in complication occurrences between treatment arms were statistically significant depending on the distribution of sample sizes. When incorporating the cost of complications into total perioperative and lifetime medical costs, costs were added according to rates observed in the clinical trials, regardless of whether those rates had statistically significant differences between arms.
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Results |
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Resource utilization
With few exceptions, patients who received aprotinin consumed fewer resources than did placebo patients. The mean units of blood products, time in CABG surgery, postoperative ICU length of stay, and post-ICU length of stay are presented in Table 2. A significant and dose-dependent reduction in transfusion requirements was observed for patients administered aprotinin relative to placebo. In both primary and repeat CABG procedures, compared with placebo, administration of full-dose aprotinin was associated with a significant reduction of time in surgery. The shorter ICU length of stay observed in the full-dose aprotinin group was not significant relative to that of placebo. The effect of half-dose aprotinin on time in surgery and ICU length of stay was inconsistent among primary and repeat procedures. No significant differences in post-ICU length of stay were observed among the groups.
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Results from the lifetime cost analysis for full-dose aprotinin, half-dose aprotinin, and placebo CABG patients are also listed in Table 4. For primary CABG, the estimated per-patient incremental lifetime cost due to stroke for the full-dose, half-dose, and placebo cohort is $1,006, $930, and $1,520, respectively. The incremental lifetime costs due to stroke for primary CABG patients who received a full- and half-dose of aprotinin are $514 and $590 less, respectively, than for placebo patients. For repeat CABG the estimated per-patient incremental lifetime costs due to stroke for the full-dose, half-dose, and placebo cohort are $508, $1,295, and $4,444, respectively. The incremental lifetime costs due to stroke for repeat CABG patients who received a full- and half-dose of aprotinin are $3,936 and $3,149 less, respectively, than for that of placebo patients.
For primary CABG, the estimated per patient incremental lifetime costs due to AMI for the full-dose, half-dose and placebo cohort are $1,084, $1,811, and $1,099, respectively. The incremental lifetime costs due to AMI for primary CABG patients were $15 lower for full-dose and $712 higher for half-dose aprotinin when compared with placebo. For repeat CABG patients, the estimated per-patient incremental lifetime costs due to AMI were $3,351 for full-dose aprotinin patients, $4,188 for half-dose aprotinin patients, and $3,401 for placebo patients.
The total lifetime CABG cost is the sum of the total perioperative CABG cost, the cost of aprotinin, and the total lifetime stroke and AMI complication costs for each treatment arm. For primary CABG patients, the estimated total lifetime costs were $27,551 for full-dose patients, $27,685 for half-dose patients, and $27,737 for placebo patients. The total lifetime CABG costs were $186 lower for full-dose patients and $51 lower for half-dose patients than placebo patients. For repeat CABG patients, the estimated total lifetime costs were $32,711 for full-dose patients, $34,272 for half-dose patients, and $38,755 for placebo patients. The total lifetime CABG costs were $6,044 lower for full-dose patients and $4,483 lower for half-dose patients than placebo patients. The lower total lifetime costs among repeat CABG patients who received either dose of aprotinin are significant relative to that of placebo.
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentConclusionsAcknowledgmentsReferences |
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The incremental in-hospital complication costs were small, contributing $80 or $330 to total perioperative cost depending on treatment arm. The incremental lifetime costs of the complications were substantial, adding approximately 10% to the total cost of primary CABG and 25% to the cost of reoperative CABG for placebo patients.
In primary CABG patients, the full-dose regimen resulted in further cost savings compared with placebo primarily due to the difference in the incidence of stroke without a difference in the incidence of AMI. For half-dose patients, the lifetime cost savings from the difference in the incidence of stroke were offset by an increase in lifetime costs for AMI. Both regimens remained cost neutral with the additional consideration of lifetime cost.
In reoperative CABG patients, the full-dose regimen more substantially reduced lifetime cost compared with placebo again primarily due to stroke reduction without a difference in the incidence of AMI. For half-dose patients, the savings due to stroke reduction were partially eroded by an increased cost of AMI compared with placebo. Both regimens produced additional cost savings when lifetime costs were considered.
Although cost analyses of aprotinin use in CABG have been reported previously, the current investigation is unique in evaluating costs in a large cohort administered full-dose or half-dose aprotinin, in both primary and repeat CABG. Pharmacoeconomic studies evaluating half-dose aprotinin in high-risk patients undergoing cardiopulmonary bypass have reported cost savings relative to no aprotinin [20], full-dose aprotinin [19], and other antiinflammatory strategies [21]. These past evaluations were not as comprehensive as the present analysis, incorporating only costs for blood products, in addition to costs for length of stay [19–21], operative time [19, 20], reoperation for bleeding [19], and hospital charges [21]. In a consecutive cohort of open heart surgery patients treated with no, half-dose, or full-dose aprotinin, investigators reported that although both aprotinin doses reduced blood product use and operating room time, half-dose resulted in a significant cost savings relative to no aprotinin [22]. In repeat CABG patients, investigators reported that blood costs for patients treated with full-dose aprotinin were greater than for those treated with epsilon aminocaproic acid, and suggested that half-dose aprotinin may provide a significant cost advantage [23]. The current analysis, by evaluating all significant resource-use predictors including complications in a multivariable mode, and by considering the lifetime impact of in-hospital events, resolves many of the limitations of these previous studies. Interestingly, a recent report on cost modeling from the United Kingdom described the impact of aprotinin use in CABG surgery from the perspective of lost opportunity, reporting that aprotinin use reduced costs directly by decreasing transfusion requirements, and indirectly by reducing waiting time for the procedure [24].
Limitations
As with most clinical trials before the mid-1990s, cost information was not gathered when the aprotinin clinical trials were conducted. The initial strategy for this cost study, gathering cost data ex-post from nine sites that participated in the clinical trials, also was not feasible, as several important categories of patient costs were omitted, data were missing, and large variations in cost for a given resource were apparent. Instead, the model-based approach was pursued, resulting in a standardized estimate of costs approximating the process of care for CABG patients at medical centers that participated in the clinical trials. As costs were imputed from Duke University Medical Center data, and unit total costs vary among institutions and depend on their respective cost structures, direct extrapolation of results to other institutions may not be possible. However, the general results will be valid for all institutions due to the utilization of a bottom-up cost allocation system (Eclipsys Corp, Boca Raton, FL) to create the model. A second limitation is that some resource utilization in the clinical trials was prescribed by protocol, and thus is not subject to variation resulting from clinical practice. In particular, a mandated minimal hospital length of stay to complete protocols would limit the ability of this primary cost driver to vary between study arms. As the aprotinin study groups generally had fewer complications and fewer transfusions, this limitation would likely artificially add resource use and costs to the aprotinin groups compared with placebo. A third limitation of this study is that estimates of expected lifetime cost of stroke and AMI were based on costs observed in the general elderly population. However, the impact of this limitation is applied across all treatment arms, and any effect on the cost estimates is expected to be minimal on a comparative basis. Similarly, the study is limited in that the procedures were not performed contemporaneously, and interval changes in surgical practice and costs have occurred; however, the results maintain comparability, as all arms should be similarly affected.
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Conclusions |
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TopAbstractIntroductionMaterial and methodsResultsCommentConclusionsAcknowledgmentsReferences |
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Acknowledgments |
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TopAbstractIntroductionMaterial and methodsResultsCommentConclusionsAcknowledgmentsReferences |
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Appendix |
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The model describing the relationship between total perioperative cost (C) and the explanatory variables takes the following general form:
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Model-fitting procedures led us to exclude two variables: amount of time anesthesia was administered, and the New York Heart Association function class of the patient. Tests for multicolinearity on the remaining variables discussed above were low to moderate. As usual with cost data, total costs of the Duke University Medical Center patients were not normally distributed. Therefore, the regression model was executed on log-transformed total cost values to normalize the distribution. To untransform the resulting log parameter estimates into nominal dollar values, the smearing technique outlined by Duan was used [25]. Results of the cost regression model are provided in the following table:
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a Statistically significant difference (p 
0.05).
Physician cost data were not collected in the trials, nor were they available in the Duke University Medical Center data. Because all patients received a CABG, the cost of performing the surgery was assumed to be the same across treatment arms and thus was not included in the computation of perioperative costs. However, the incremental physician consultation and surgery costs induced by reoperation stroke and AMI were taken into consideration. Medicare physician reimbursement for reexploration for bleeding (CPT 35820) is assigned a relative total value of 18.87, which, with the time-relevant conversion factor, results in the amount of $726. Medicare physician reimbursement for initial inpatient neurological consultation (CPT codes 99251 to 99255) ranged from $46 to $202, and follow-up consultation (CPT codes 99261 to 99263) ranged from $26 to $72, depending on the patient's condition and how comprehensive an exam the patient required. Thus, the physician cost associated with a stroke was estimated to be $173, the sum of the mean initial and follow-up physician consultation costs. Additional physician work was not allocated for the treatment of perioperative AMI, because it was assumed that it was provided by the surgeon as part of the global surgical fee. Physician cost was added to the hospital cost estimated by the regression equation to derive the total incremental cost incurred by reoperation and stroke patients. Preset costs for full-dose and half-dose aprotinin were added to the total cost estimated by the regression model for each treatment arm. It was assumed that the cost of a complication was not significantly influenced by the treatment group.
Downstream cost of stroke
Research from the Stroke Prevention PORT generated age group–, gender-, and race-specific monthly direct costs (discounted at 3%) and survival probabilities for a random 20% sample of Medicare enrollees in 1991 who suffered an ischemic stroke. Respective monthly costs and survival probabilities were multiplied, and the resulting expected monthly costs were then aggregated to derive the expected lifetime direct cost of ischemic stroke patients. The same calculation was also made on a comparison sample of nonstroke individuals to infer their expected lifetime direct cost for health care. The expected lifetime direct cost of the nonstroke individuals was subtracted from the expected lifetime direct cost of ischemic stroke patients to derive the following net expected lifetime direct cost of ischemic stroke patients between the ages of 65 and 69 years (the age bracket providing the closest fit to the age of most subjects in the clinical trials): $55,707 for white males, $54,635 for nonwhite males, $65,991 for white females, and $68,138 for nonwhite females. Cowper and associates estimated that 95% of CABGs performed on Medicare enrollees in 1990 were on whites and 5% were on nonwhites [26]. These gender and race percentages were applied as weights to calculate the aggregate net expected lifetime direct cost of ischemic stroke. Lastly, the 1991 cost estimate of $57,011 was inflated using the medical care component of the CPI to a value of $87,393 in 2001 dollars to derive the net discounted expected lifetime direct cost of ischemic stroke.
Downstream AMI cost
Using a data set containing a 0.3% random sample of all Medicare enrollees for 1991 who had not suffered a stroke, 857 white males, 77 nonwhite males, 866 white females, and 84 nonwhite females between the ages of 65 and 69 years who were hospitalized with a primary diagnosis of AMI were identified. Employing the same incremental cost analysis approach we applied to lifetime stroke costs, we estimated the net expected lifetime direct cost of AMI to be $18,714 for white males, $16,704 for nonwhite males, $19,248 for white females, and $16,929 for nonwhite females. Applying the same gender and race weights employed in the stroke cost calculation, the net discounted expected lifetime direct cost of AMI was estimated to be $28,480 in 2001 dollars.
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References |
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TopAbstractIntroductionMaterial and methodsResultsCommentConclusionsAcknowledgmentsReferences |
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  T. M. Sundt The demise of aprotinin: Our share of the blame. J. Thorac. Cardiovasc. Surg., April 1, 2008; 135(4): 729 - 731. [Full Text] [PDF]
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